Zhang Liwen, Bushel Pierre R, Chou Jeff, Zhou Tong, Watkins Paul B
The Hamner Institutes for Health Sciences, Research Triangle Park NC, USA.
Front Genet. 2012 Sep 4;3:162. doi: 10.3389/fgene.2012.00162. eCollection 2012.
The ability to identify mechanisms underlying drug-induced liver injury (DILI) in man has been hampered by the difficulty in obtaining liver tissue from patients. It has recently been proposed that whole blood toxicogenomics may provide a non-invasive means for mechanistic studies of human DILI. However, it remains unclear to what extent changes in whole blood transcriptome mirror those in liver mechanistically linked to hepatotoxicity. To address this question, we applied the program Extracting Patterns and Identifying co-expressed Genes (EPIG) to publically available toxicogenomic data obtained from rats treated with both toxic and subtoxic doses of acetaminophen (APAP). In a training set of animals, we identified genes (760 at 6 h and 185 at 24 h post dose) with similar patterns of expression in blood and liver during APAP-induced hepatotoxicity. The pathways represented in the coordinately regulated genes largely involved mitochondrial and immune functions. The identified expression signatures were then evaluated in a separate set of animals for discernment of APAP exposure level or APAP-induced hepatotoxicity. At 6 h, the gene sets from liver and blood had equally sufficient classification of APAP exposure levels. At 24 h when toxicity was evident, the gene sets did not perform well in evaluating APAP exposure doses, but provided accurate classification of dose-independent liver injury that was evaluated by serum ALT elevation in the blood. Only 38 genes were common to both the 6 and 24-h gene sets, but these genes had the same capability as the parent gene sets to discern the exposure level and degree of liver injury. Some of the parallel transcript changes reflect pathways that are relevant to APAP hepatotoxicity, including mitochondria and immune functions. However, the extent to which these changes reflect similar mechanisms of action in both tissues remains to be determined.
从患者获取肝脏组织存在困难，这阻碍了我们识别人类药物性肝损伤（DILI）潜在机制的能力。最近有人提出，全血毒理基因组学可能为人类DILI的机制研究提供一种非侵入性方法。然而，全血转录组的变化在多大程度上反映了与肝毒性有机制联系的肝脏变化仍不清楚。为了解决这个问题，我们将提取模式和识别共表达基因（EPIG）程序应用于从用毒性和亚毒性剂量对乙酰氨基酚（APAP）处理的大鼠获得的公开可用毒理基因组数据。在一组训练动物中，我们鉴定了在APAP诱导的肝毒性期间血液和肝脏中具有相似表达模式的基因（给药后6小时有760个，24小时有185个）。协同调节基因所代表的途径主要涉及线粒体和免疫功能。然后在另一组动物中评估所鉴定的表达特征，以辨别APAP暴露水平或APAP诱导的肝毒性。在6小时时，来自肝脏和血液的基因集对APAP暴露水平的分类同样充分。在24小时毒性明显时，基因集在评估APAP暴露剂量方面表现不佳，但能准确分类与剂量无关的肝损伤，该损伤通过血液中血清谷丙转氨酶（ALT）升高来评估。6小时和24小时的基因集只有38个基因相同，但这些基因与母基因集具有相同的辨别暴露水平和肝损伤程度的能力。一些平行的转录变化反映了与APAP肝毒性相关的途径，包括线粒体和免疫功能。然而，这些变化在多大程度上反映了两种组织中相似的作用机制仍有待确定。
